Our results further suggest that the reduced efficacy of muMAb 4D5 in Fo2-1282 brain grafts compared with mammary tumors may arise from incomplete pathway suppression or hyper-activation of downstream signal transduction pathways, as combined treatment with muMAb 4D5 and the brain-penetrant PI3K/mTOR inhibitor GNE-317 was more effective than either drug alone. This evidence concerns the gene MTOR and breast cancer.